tbuckley/cabot-search huggingface dataset:
Unveiling the prognostic significance of BCL6+/CD10+ mantle cell lymphoma: A systematic analysis.
Authors: Dan Ran Castillo, Daniel Park, Won Jin Jeon, Esther G Chong, Bowon Floyd Joung, Jin Hyun Floyd Moon, Bryan Pham, Jae Lee, Zeeshan Siddiqui, Anthony Loc Nguyen, Ke Kurt Zhang, Huynh Le Cao
Journal: Journal of Clinical Oncology (2023)

7572 Background: Mantle cell lymphoma (MCL) is heterogenetic B-cell neoplasm that characterized by the presence of the IgH/CCND1 translocation. The significance of CD10 expression in MCL is not fully understood. The co-expression of CD10 and BCL6 in MCL is rare requiring further investigation to determine its clinical significance. This meta-analysis aims to examine the relationship between MCL variants and their cellular behaviors and clinical outcomes. Methods: A search of the GDC and dbGaP database was conducted using the PICOS model and PRISMA guidelines to retrieve survival data. Overall survival (OS) data was pooled from multiple studies and analyzed using the R programming package survival and a log-rank test was performed to compare OS. Mean differences between BCL6+ vs. BCL6- for individual studies were calculated and combined to minimize batch effects. Summary statistics across studies were obtained by averaging mean differences and pooling individual standard deviations. The correlation between CD10 and BCL6 was tested using Fisher's exact test, with a significance level of 0.05. Results: The analysis included a total of 537 patients (425 males and 112 females), with a median age at diagnosis of 69 years in CD10+ MCL and 61.5 years in CD10- MCL. Out of the 537 patients, 70 were CD10+ positive, and BCL6 positivity had an odds ratio of 5.11 [95% CI [2.49, 10.46]; p = 0.0000286) for CD10 positivity compared to CD10 negativity. The subgroup analysis revealed a higher frequency of blastoid/pleomorphic/small variants in BCL6+/CD10+ MCL. BCL6 positivity was associated with worse OS, independent of CD10 expression (median OS of 14 months in BCL6+ MCL vs. 43 months in BCL6- MCL; p = 0.01). The co-expression of BCL6 and CD10 was associated with a shorter median OS (22 months in BCL6+CD10+ vs. 55 months in BCL6-CD10+, p = 0.01) and significantly higher mitotic index (Ki67%) compared to BCL6-/CD10+ MCL (mean Ki67% of 63.13 ± 19.45% vs. 45 ± 21.69%, p &lt; 0.01). The forest plot analysis showed that BCL6 expression was correlated with a significantly higher Ki67% (difference of 24.29; p = 0.0094). Conclusions: Our meta-analysis found that BCL6 expression correlates with CD10 positivity in MCL variants and has a negative impact on prognosis, independent of CD10 expression. Higher Ki67% levels in BCL6+ MCL compared to BCL6- MCL support the prognostic value of the BCL6+ immunophenotype in MCL variants. Prognostic scoring systems adjusted for BCL6 expression should be incorporated into MCL management. Targeted therapies against BCL6 may offer potential treatment options for MCL subtypes. [Table: see text]
The peripheral TCR repertoire diversity indexes can be used as an independent indicator for long term survival rate of ovarian cancer patients.
Authors: Kaiyu Fu, Xin Yang, Kemin Li, Rutie Yin
Journal: Journal of Clinical Oncology (2023)

e17558 Background: According to GLOBOCAN 2020 data, ovarian cancer (OC) ranks 19th in incidence and 15th in mortality with a rate of 1.6% and 2.1%, respectively, High-grade serous OC is the most common sub-type of malignant ovarian tumors, remains the leading cause of cancer-related death among all gynecological cancers in the developed parts of the world. In the United States in 2016, 5-year survival rate was only 10-25% in stage III or IV OC patients, and there was considerable variability in survival in an advanced stage. At present, there is no reliable molecular marker to identify patients with better or worse prognosis. As is known to all, the adaptive immune system defends the body against different foreign antigens, using two main types of antigen receptors: T-cell receptors (TCRs) and antibodies. Now we use high-throughput sequencing approach to analyze the expressed TCRβ repertoires in the peripheral blood of OC patients and healthy women donors. Methods: The experimental design and participant recruitment were approved by Medical Ethics Committee of West China Second University Hospital (Ethics Approval for Research: 2022). Total RNA was extracted from PBMC using TRIZOL reagent. High through put sequencing of the TCRβ gene, assignment of the Vβ, Dβ, and Jβ germline gene, and TCR diversity indexes analyses were conducted essentially following our previously published protocols. Statistical analysis and graph drawing were performed using R language (R 4.0.3). Results: Comparison of the TCR repertoires between the 232 OC patients (OC group) and the 250 healthy women donors (HD group) revealed significant differences. For examples, the VJ combinations of the OC group were distinct from those of the HD group. In addition, the TCR repertoire diversity indexes of the OC group were significantly lower than those of the HD group ( p &lt; 0.001), including D50s, Simpson indexes, the number of highly expressed clones (HECs), and the frequencies of the largest TCR clones. As reported before, the TCR repertoire diversity indexes decreased gradually with increasing age in the HD group (all p &lt; 0.001). Moreover, the TCR repertoire diversities in the survival group were significantly higher than those in the death group (D50: p = 0.0342; the number of HECs: p = 0.0414). Using as the cut off value, the OC patients with D50 &lt; 0.032 had significantly higher mortality rates compared to the OC patients with D50 &gt; 0.032 ( p = 0.0019). Similarly, using the numbers of HECs or the frequencies of the largest TCR clones can also distinguish OC patients in long term survival. Conclusions: Analyzing the peripheral TCR repertoires in the OC and HD revealed significant differences, and the peripheral TCR repertoire diversity indexes may be used as a potential predictor for long term survival for ovarian cancer.
Results of the multicenter phase II FRAIL-IMMUNE trial evaluating the efficacy and safety of durvalumab combined with weekly paclitaxel carboplatin in first-line in patients (pts) with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) not eligible for cisplatin-based therapies.
Authors: Jerome Fayette, Claire Cropet, Julien Gautier, Clemence Toullec, Mickael Burgy, Amandine Bruyas, Christian Sire, Aurelie Lagrange, Florian Clatot, Benoit Calderon, Marie Vinches, Mariana Iacob, Laurent Martin, Eve Marie Neidhardt Berard, Marie-Christine Kaminsky, Damien Vansteene, Sébastien Salas, Anne Champagnac, David Pérol, Jean Bourhis
Journal: Journal of Clinical Oncology (2023)

6003 Background: For pts with R/M SCCHN, new standard of care (SoC) has been recently established with pembrolizumab either alone or combined with platin-5FU (KN 048 – median Overall Survival (OS): 13 months when combined). For pts who need chemotherapy, platinum-5FU-pembrolizumab as first-line treatment appears associated with substantial toxicity that precludes its use in fragile patients. In this context, we investigated the efficacy and tolerance of PDL-1 inhibition with durvalumab combined with weekly carboplatin-paclitaxel as first-line treatment in frail R/M SCCHN pts. Methods: This single-arm phase II study enrolled pts in first-line of their R/M SCCHN and not eligible to standard cisplatin-based CT with an ECOG PS of 0 or 1. Pts received 4 cycles of CT (carboplatin AUC2; paclitaxel 80mg/m² both at D1, D8, D15) and durvalumab (D) 1500mg repeated every 4 weeks for a maximum of 12 months. The primary endpoint was OS Rate at 12 months (m). The study used a Fleming A’Hern design (inefficacy boundary: 47% and target efficacy: 65%), requiring 38 successes among 64 pts. Secondary endpoints were Progression-Free Survival (PFS), Time to Treatment Failure (TTF), objective response rate (ORR) and tolerance. Results: 64 pts (median age 69.5y; 90.6% males, 62.5% PS1) were included, regardless of their PDL-L1 status. Primary tumors were mainly located in oropharynx (37.5%) and larynx (28.1%) with 37.3% PD-L1 CPS≥20. 54.9% were metastatic. The efficacy rule for OS was met with 40 pts (62.5%, unilateral 95%CI: [51.5% - ]) alive at 12m. With a median follow-up of 27.1 m, median OS was 18.0 m (95% CI [11.9-NR]) and the 24m-OS rate was 45% [32%-57%]. Median PFS was 7.0 m (95% CI [5.4-9.9]) and median TTF was 6.0 m (95% CI [4.7-9]). 44/62 pts (71%) achieved an OR (11.3% complete response and 59.7% partial response). Median duration of response was 5.9 m (95% CI [3.4-9.6]). 20.3% of pts experienced G≥3 adverse events related to D, Toxicity led to permanent discontinuation of D in 3.1% of pts. No D-related death was reported. Conclusions: This study performed in fragile patients not amenable to cisplatin-based CT met its primary endpoint on OS and showed a 18 months median OS rate. This combination of durvalumab with weekly carboplatin/paclitaxel was associated with a favorable toxicity profile. Clinical trial information: NCT0372967 .
Restaging scans frequency heterogeneity in patients being treated for stage IV non-small cell lung cancer (NSCLC).
Authors: Guilherme Sacchi de Camargo Correia, Ariana Mooradian, Yujie Zhao, Yanyan Lou, Rami Manochakian
Journal: Journal of Clinical Oncology (2023)

e21161 Background: Patients with stage IV NSCLC undergo frequent restaging scans (RS). While vital to assess treatment response, RS add anxiety and financial burdens to patients. The ideal frequency of RS is unclear. The numerous treatment options available, such as targeted therapy (TT) and immunotherapy (IO), and the variability in frequency of RS in the trials that led to their approval reflect this uncertainty. Due to the lack of clear guidelines about their ideal interval in daily practice, we reviewed the heterogeneity in frequency of RS in those trials, comparing it to the reported progression-free survival (PFS). Methods: In this study, we reviewed the FDA-approved drugs for stage IV NSCLC since 10/18/2016 and selected the TT and IO. Each trial that led to approval was reviewed, collecting the frequency of RS and the median PFS for the intervention (IA) and control arms (CA). Results: 18 TT drugs and 12 IO regimens, with and without chemotherapy (chemo), were found. Among them, the frequency of RS varied from every 4 to 9 weeks (w) upfront, later modified to every 6 to 12 w until disease progression. The median PFS for both groups in the IA ranged from 2.8 to 19.4 months (m), and from 3.0 to 12.4 m in the CA. The TT group had drugs directed at 7 different mutations, and it presented more discrepancy in terms of restaging frequency. The period between RS varied from every 4 to 8 w initially, later modified to every 6 to 12 w. However, 11 of 18 trials had an interval of every 6 w. The shortest median PFS in the IA arm was 5.4 m, and 5.6 m in the CA. While the longest median PFS was 19.4 m in the IA and 12.4 m in the CA. The IO group included 5 regimens with chemo and 7 without. The interval between RS varied from 6 to 9 w originally, to every 8 to 12 w later. Yet, 8 of 12 regimens’ trials scanned patients every 6 w initially. The median PFS in the IA ranged from 2.8 to 10.3 m, and between 3.0 to 6.5 m in the CA. Conclusions: We observed notable heterogeneity among trials regarding the frequency of RS in patients treated for stage IV NSCLC. When comparing these intervals to the median PFS, we noted the shortest PFS reported is longer than most adopted intervals. This may indicate RS were obtained more frequently than needed. The increased frequency of RS raises a burden for patients and the medical system, while contributing to disparities. This finding, coupled with further comparisons between the frequency of RS in trials and in daily practice, may pave the way for prospective studies analyzing the ideal interval for RS. This can lead to a more efficacious and less burdensome strategy for patients. [Table: see text]
Randomized double-blind, placebo-controlled study of topical diclofenac in prevention of hand-foot syndrome in patients receiving capecitabine.
Authors: AKHIL Santhosh, Atul Batra, akash kumar, Raja Pramanik, Ajay Gogia, Winson Y. Cheung, Atul Sharma, Chandra Prakash Prasad, Tushar Sehgal
Journal: Journal of Clinical Oncology (2023)

12005 Background: Capecitabine induced HFS is associated with deterioration of quality of life of patients and dose of capecitabine is often reduced to manage this adverse event. Celecoxib is the only effective intervention in preventing HFS; however, its widespread use is limited due to its own safety concerns. We conducted this study to assess the efficacy of topical diclofenac in preventing capecitabine induced HFS. Methods: Patients with breast and gastrointestinal (GI) cancers, planned for capecitabine (monotherapy or combination) treatment were randomized in 1:1 to receive topical diclofenac or placebo gel for 4 cycles or until development of HFS, whichever was earlier. Stratified (male or female; capecitabine monotherapy or combination therapy) permuted variable size block randomization was done using a computer-generated random numbers sequence. Primary objective was to compare the incidence of grade 2 or higher HFS in diclofenac and placebo arms. Secondary objectives were incidence of any grade HFS, capecitabine dose changes due to HFS and self-reported adherence with application. Results: A total of 263 patients were randomized to apply topical diclofenac gel (n=130) or placebo (n=133). Baseline characteristics were similar in both the arms (Table). The incidence of grade 2 or higher HFS was 3.8% (95% CI, 1.6%-8.9%) in the diclofenac arm compared with 15.0% (95% CI, 9.9%-22.2%) in the placebo arm (P=0.003). Any grade HFS was significantly lower in the study arm compared with the placebo arm (6.1% vs 18.1%; P=0.003). A lower incidence of HFS was observed in the diclofenac arm across the subgroups (breast and GI cancers; males and females). Capecitabine dose reductions were less frequent in the diclofenac arm (3.8%) compared with the placebo arm (15%) (P=0.002). Adherence to topical treatment was similar in the diclofenac arm (96.7 +/- 19.1%) compared with the placebo arm (94.0 +/- 28.3%) (P=0.36). Other capecitabine associated adverse events, including diarrhea, mucositis, and myelosuppression were not significantly different in both the arms. Conclusions: Topical diclofenac is effective in preventing all grades of HFS in patients receiving capecitabine. Diclofenac application was also associated with lesser dose reductions of capecitabine. This trial establishes topical diclofenac as the new standard of care to prevent capecitabine associated HFS. Clinical trial information: CTRI/2021/01/030592 . [Table: see text]
Accuracy of a simplified sequencing and bioinformatics platform on genetic variant detection in patients with prostate cancer.
Authors: Deepak A. Kapoor, Ann E. Anderson, Jonathan Anderson
Journal: Journal of Clinical Oncology (2023)

e17061 Background: Consensus guidelines suggest that genetic testing is clinically indicated for prostate cancer (PCa) patients who meet certain family history, stage and histopathological grade criteria. Current next generation sequencing (NGS) diagnostics rely on capital and maintenance intensive sequencers which require highly trained technical personnel to operate. This may restrict availability of testing where specimen transport or access to personnel/capital is limited. We sought to compare results obtained using a simpler sequencer coupled with a bioinformatics platform which requires minimal maintenance and capital cost with those from more traditional NGS equipment. Methods: We compared results in detection of 10 genes recommended by NCCN PCa guidelines (ATM, BRCA1, BRCA2, CHEK2, MLH1, MSH2, MSH6, PALB2, PSM2, and HOXB13) between the Oxford Nanopore Technologies MinION to the Illumina NextSeq sequencer. All samples were sequenced in a depth greater than 50x. Bioinformatics for the Illumina sequencer was performed using Illumina’s TruSight Hereditary Cancer panel. As the MinION reads long DNA fragments, and cancer diagnostics is focused on short exon sequencing, we used the CorrSeq Dx by Foresee Genomics to create long DNA molecules consisting of several tandem repeats of short DNA fragments separated by sequences recognized by automated bioinformatics software. Statistical analysis was performed using Cohen’s kappa test. This IRB-exempt study was conducted in accordance with the Declaration of Helsinki. Results: We detected using 380 variants in 13 patients on the Illumina platform and 379 (3 false negatives, 2 false positives) variants on the same patients using the MinION sequencer with CorrSeq Dx assay. The positive predictive value and sensitivity for the simplified platform was 99.5% (375/(375+2)) and 99.2% (375/(375+3)), respectively. The demonstrated accuracy of the simplified process was 99.9% (Cohen's kappa &gt; 0.99). Conclusions: Thisl data suggests that a simpler sequencing solution with appropriate bioinformatics could allow clinical laboratories with limited technical and capital resources to perform germline and possibly somatic testing in-house; use of this technology may also serve to reduce costs for labs currently performing these tests. While some labs or clinics can outsource their NGS diagnostics if such commercial options are available, these options may not be possible where transport of specimens is logistically difficult or if access to technology is limited. A simpler process for NGS testing could improve access to guideline-based care in both remote and economically disadvantaged areas, resulting in better treatment outcomes as well as increased global healthcare equity. Further testing of this technology in prostate cancer as well as other disease states is warranted to fully understand its potential impact on patient care.
Trends of using immune checkpoint inhibitors near end of life in limited resources setting: Experience of single cancer center in the MENA region.
Authors: Kamal Hosni Al-Rabi, Mohammad Maakoseh, Saad Jaddoua, Samer Salah, Omar Alta'ani, Abeer Yasin, Dalia Alrawshdeh, Yosra almasri, Omar Shamiah, Akram Al-Ibraheem, Hikmat Abdel-Razeq
Journal: Journal of Clinical Oncology (2023)

6566 Background: Immune checkpoint inhibitors (ICIs) are standard of care nowadays in the treatment of many solid tumors as single agent or in combination. Recent literature suggested increased use of ICI near end of life; our aim was to find the characteristics of the patients who received ICI 30 days or less before their death. Methods: Data of patients with advanced solid tumors who have (ICI) therapy and died with disease were retrospectively retrieved. Patients were categorized into those dying within 30 days of the last dose of ICI and those receiving the last dose of ICI more than 30 days before death. Variables of potential interest were compared between the two groups by the Chi-square and independent sample t-tests as appropriate. Results: A total of 411 patients were included in this analysis; 135 (33%) received the last dose of ICI within 30 days of death and 276 (67%) received their last dose more than 30 days before death. Major cancer types included: lung (n=214; 52%), kidney (n=61; 15%), melanoma (n=44; 11%), head and neck (n=41; 10%), and others (n=14; 3%). Patients’ characteristics: median age = 58, majority were males (310; 75%), 105 (26%) had ECOG PS ≥3, and 147 (36%) had brain metastasis. Patients who received the last dose of ICI within 30 days of death had more frequent ICU admissions (50 (37%) vs. 60 (22%), p=0.001, and were less likely to die under the care of the hospice care service (22 patients (16%) vs. 84 (31%), p=0.001. In addition, patients who received the last dose of ICI within 30 days of death were more likely to have a full code status (89 (66%) vs. 147 (53%), p=0.015, and have received a lower number of doses of ICI treatments (mean number of doses: 4.2 vs. 6.5 doses, p=0.001). We did not observe any significant difference between the two groups regarding type of cancer, age, gender, ECOG PS, presence of brain metastasis, number of hospital admissions, dying inside hospital, and number of emergency room visits. Conclusions: Immune checkpoint inhibitors may be overused near end of life which leads to minimal clinical benefits, less likelihood of dying under hospice care, and utilization of ICU resources.
Phase 2 clinical trial of the proautophagic drug ABTL0812 combined with paclitaxel and carboplatin in first-line patients with advanced squamous non-small cell lung carcinoma.
Authors: Joaquim Bosch-Barrera, Teresa Moran, Purificación Estévez-García, Paloma Martín-Martorell, Renaud Sabatier, Ernest Nadal, Jose M. Lizcano, Oriol Pedrós-Gámez, Héctor Pérez-Montoyo, Marc Yeste-Velasco, Carles Domenech, Jose Alberto Alfon
Journal: Journal of Clinical Oncology (2023)

9059 Background: ABTL0812 induces the inhibition of Akt/mTOR pathway by upregulation of TRIB3 protein, an endogenous Akt inhibitor, and promotes endoplasmic reticulum (ER) stress. As a result, ABTL0812 induces cytotoxic autophagy that leads to specific death of cancer cells, without affecting non-tumor cell viability. A Phase II clinical trial was designed where ABTL0812 was evaluated in combination with paclitaxel and carboplatin in first-line patients with advanced squamous non-small cell lung cancer (NSCLC). Methods: ABTL0812 was administered 1300 mg TID orally with 175 mg/m 2 paclitaxel and AUC5 carboplatin every 3 weeks, for up to 8 cycles, followed by ABTL0812 as a maintenance until disease progression or unacceptable toxicity. The study enrolled patients with non-irradiable IIIb stage or stage IV squamous NSCLC. Primary endpoint was overall response rate (ORR) by RECIST criteria v.1.1. Secondary endpoints were progression free survival (PFS), overall survival (OS), duration of response (DOR), safety and tolerability according to CTCAE v4.03, pharmacokinetics (PK) of ABTL0812 enantiomers ((-)-ABTL and (+)-ABTL) and pharmacodynamics assessed by two surrogate blood biomarkers: TRIB3 and CHOP. Results: Forty patients were included; median age was 66.1 years old; 90% men/10% women; 100% ECOG 0-1; 30% current smokers/67.5% former smokers and 37.5% had received prior chemotherapy &gt; 12 months before inclusion. 39 patients had at least 1 adverse event (AE), anemia appeared in 32.5% of the patients (5.0% grade 3), neutropenia in 27.5% (25% grades 3-4) and thrombocytopenia in 17.5% of the patients (2.5% grade 3). For non-hematological AEs, asthenia was reported in 62.5% of the patients (2.5% grade 3); diarrhea in 45% (no grade 3-4) and nausea in 37.5% (5% grades 3-4). Twenty-five patients reach the primary endpoint for efficacy evaluation. ORR was 52.0% (95% CI 34.2-65.9) and 32.0% of the patients had stable disease. Median OS was 22.5 months (10.4-NC), median progression free survival 6.2 months (4.4-8.8), and DOR 5.1 months (3.9-7.4). Area under the curve (µg·h/ml) for (-)-ABTL and (+)-ABTL were 39.0±12.3 and 17.1±6.3 respectively, maximal concentrations (µg/ml) were 6.4±2.6 and 5.1±2.2 and minimum concentrations (µg/ml) 2.2±1.5 and 0.8±1.3. TRIB3 and CHOP PD biomarkers were induced by the treatment. Conclusions: The combination of ABTL0812 with paclitaxel and carboplatin shows survival outcomes that compare favorably with historical controls in squamous-NSCLC with an acceptable safety profile. PK analysis is compatible with drug activity, and pharmacodynamic analysis shows drug engagement. Clinical trial information: NCT03366480 .